Phase I/II Trial of Simultaneous Whole-Brain Irradiation and Dose-Escalating Topotecan for Brain Metastases |
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Authors: | PD Martin Kocher MD Hans-Theodor Eich Robert Semrau Semi Aykut Güner Rolf-Peter Müller |
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Institution: | 2. Department of Radiotherapy, University of Cologne, Joseph-Stelzmann-Stra?e 9, 50924, K?ln, Germany 1. Department of Radiation Oncology, University Hospital, University of Cologne, Cologne, Germany
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Abstract: | BACKGROUND AND PURPOSE: Topotecan penetrates the blood-brain barrier and sensitizes tumor cells against radiation. A phase I/II dose-escalating trial of repetitive daily i. v. topotecan application simultaneously with whole-brain irradiation (WBRT) was conducted to estimate toxicity, maximum tolerated dose and survival in patients with inoperable brain metastases. PATIENTS AND METHODS: In 47 patients suffering from previously untreated brain metastases, topotecan was applied on a daily i. v. schedule simultaneously with WBRT (36 Gy/3-Gy fractions). The infusion schedule started at the beginning of WBRT and was discontinued during weekends. Each infusion was completed within 1-2 h before irradiation. In a dose-finding study, topotecan was escalated from 5 x 0.5 mg/m(2), 8 x 0.5 mg/m(2), 12 x 0.5 mg/m(2) to 12 x 0.6 mg/m(2). RESULTS: Altogether, 38/47 patients (81%) completed the prescribed schedule. Leukopenia and thrombocytopenia were dose-limiting. Grade 3/4 hematologic toxicity occurred in 5/32 chemona?ve patients (16%) and 7/15 patients (47%) with previous chemotherapy. At 12 x 0.6 mg/m(2), 2/4 patients experienced grade 4 leukopenia/thrombopenia. Nonhematologic toxicities were generally mild to moderate and unrelated to topotecan. Response evaluation was possible in 26/47 patients, overall response rate was 58% (CR complete remission] 5/26, PR partial remission] 10/26, NC no change] 8/26). Median survival amounted to 5.1 months. In 15/42 patients (36%), brain metastases were the dominant cause of death. CONCLUSION: For a daily topotecan schedule simultaneous to WBRT, the maximum tolerated dose is 12 x 0.5 mg/m(2) in chemona?ve patients. For chemo-pretreated patients, daily doses should be reduced to 0.4 mg/m(2). A phase III trial has now been started to find out whether WBRT + topotecan increases survival compared to WBRT alone. |
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